Neuroblastoma: telomere maintenance mechanisms (telomerase activation, ATRX/DAXX loss, ALT)

history/disorders/Neuroblastoma/2026-10-21T101350Z-claude-code-1e2920.yaml

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+history_version: 1
+target:
+  kind: disorder
+  slug: Neuroblastoma
+  path: kb/disorders/Neuroblastoma.yaml
+session:
+  id: 2026-10-21T101350Z-claude-code-1e2920
+  timestamp: '2026-10-21T10:13:50Z'
+  actors:
+  - type: ai_agent
+    name: claude-code
+    model: claude-opus-5-5
+    agent_tool: claude-code
+    agent_version: 2.1.241
+links:
+  issues:
+  - https://github.com/monarch-initiative/dismech/issues/14976
+  prs: []
+  urls: []
+events:
+- type: EDIT
+  outcome: changed
+  sections:
+  - pathophysiology
+  - genetic
+  - description
+  - references
+  - evidence
+  summary: Add telomere maintenance mechanism nodes and evidence
+  details: |
+    Added the telomere maintenance mechanism layer to the neuroblastoma entry, on top of the TERT Rearrangement and ATRX Mutation genetic records added in #7114.
+
+    Pathophysiology. Four new nodes: Telomerase Activation (genes TERT; molecular function GO:0003720 telomerase activity, increased; GO:0007004; conforms to enabling_replicative_immortality#Telomere Maintenance Reactivation), Reduced ATRX/DAXX Complex Abundance (genes ATRX; GO:0140658 ATP-dependent chromatin remodeler activity, decreased), Alternative Lengthening of Telomeres (GO:0000722; no conformance, because the module's ALT anchor exists only in open PR #13924) and Unlimited Replicative Potential (GO:0008283, the binding of its anchor; conforms to enabling_replicative_immortality#Replicative Immortality). New edges: MYCN-Driven Proliferation -> Telomerase Activation (intermediate: increased TERT transcription driven by amplified MYCN), Telomerase Activation -> Unlimited Replicative Potential, Reduced ATRX/DAXX Complex Abundance -> Alternative Lengthening of Telomeres (intermediate: loss of ATRX/DAXX-dependent H3.3 deposition at telomeric repeats) and Alternative Lengthening of Telomeres -> Unlimited Replicative Potential. Counter-evidence is recorded as REFUTE items: Dagg 2017 (PMID:28636942; a high-risk subset without telomere lengthening activity) on Unlimited Replicative Potential, and Koneru 2020 (PMID:32291317; MYCN-amplified tumours with low TERT expression, and MYCN overexpression not overcoming TERT repression) on the MYCN edge.
+
+    Genetic records. ATRX Mutation: notes rewritten; the unsourced 'treatment-refractory' and 'essentially absent in infants' were replaced by statements scoped to Sun 2026 (PMID:42558321), Kurihara 2014 (PMID:25487495) and Cheung 2012 (PMID:22416102), and six evidence items were added. The existing PMID:22416102 age item's explanation was corrected: whole-genome sequencing covered 40 of the 104 patients (the other 64 by PCR and Sanger), and its pointer to an adolescent/young-adult subtype framing was dropped along with the notes rewrite; directness and quote_role were added after assessment. TERT Rearrangement: the notes and the first item's explanation were reworded from 'three alternative routes to telomere maintenance' to the two-mechanism framing, with TERT rearrangement as a route into telomerase activation.
+
+    Description and references. The telomere sentence of the top-level description now names the two mechanisms, defines the third telomerase route as high TERT expression without either alteration, and scopes the chemotherapy-response finding to large ATRX deletions and truncating mutations. In references, the bioRxiv preprint DOI:10.1101/2022.08.16.504100 was replaced by its published version, PMID:39635126; the preprint's cache file is left in place, uncited.
+
+    Totals: 54 new evidence items; 15 PMIDs new to the entry (38 in all).
+
+    Not done. No ALT conformance until #13924 merges (follow-up: add it and re-anchor Leiomyosarcoma's ALT node to the same anchor). No variant_origin on any new node, so the entry stays NO_ORIGIN for check-cancer-origin. No telomere-directed treatments. Phenotypes are not yet wired to these nodes.
+
+    Validation: just validate, validate-terms, count-verified-snippets (106/106), validate-disorders, the offline gates, check_gene_activity_grounding against origin/main, node_classes --verify-kb, prose-figure-audit (no new flags). A four-lens pre-review with two independent verifiers per finding was run before the PR, and the findings both verifiers upheld were applied, including the REFUTE regrades.

references_cache/PMID_24792489.md

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+---
+reference_id: PMID:24792489
+extractor_version: 1
+title: Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations.
+authors:
+- Farooqi AS
+- Dagg RA
+- Choi LM
+- Shay JW
+- Reynolds CP
+- Lau LM
+journal: J Neurooncol
+year: '2014'
+doi: 10.1007/s11060-014-1456-8
+keywords:
+- "Cell Line, Tumor"
+- Gene Amplification
+- Humans
+- N-Myc Proto-Oncogene Protein
+- "Nuclear Proteins/genetics, metabolism"
+- "Oncogene Proteins/genetics, metabolism"
+- Signal Transduction/genetics
+- "Telomere/genetics, metabolism"
+- Telomere Homeostasis
+- "Tumor Suppressor Protein p53/genetics, metabolism"
+publication_types:
+- Journal Article
+- "Research Support, N.I.H., Extramural"
+- "Research Support, Non-U.S. Gov't"
+content_type: abstract_only
+full_text_attempted: true
+---
+
+# Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations.
+**Authors:** Farooqi AS, Dagg RA, Choi LM, Shay JW, Reynolds CP, Lau LM
+**Journal:** J Neurooncol (2014)
+**DOI:** [10.1007/s11060-014-1456-8](https://doi.org/10.1007/s11060-014-1456-8)
+
+## Content
+
+Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase-negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway.

references_cache/PMID_25487495.md

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+---
+reference_id: PMID:25487495
+extractor_version: 1
+title: Clinical features of ATRX or DAXX mutated neuroblastoma.
+authors:
+- Kurihara S
+- Hiyama E
+- Onitake Y
+- Yamaoka E
+- Hiyama K
+journal: J Pediatr Surg
+year: '2014'
+doi: 10.1016/j.jpedsurg.2014.09.029
+keywords:
+- "Adaptor Proteins, Signal Transducing/genetics"
+- Adolescent
+- Child
+- "Child, Preschool"
+- Co-Repressor Proteins
+- DNA Helicases/genetics
+- DNA Mutational Analysis
+- Female
+- Humans
+- Infant
+- "Infant, Newborn"
+- Male
+- Molecular Chaperones
+- Mutation
+- "Neoplasm Recurrence, Local/genetics"
+- Neuroblastoma/genetics
+- Nuclear Proteins/genetics
+- Prognosis
+- Telomere Homeostasis
+- X-linked Nuclear Protein
+publication_types:
+- Journal Article
+- "Research Support, Non-U.S. Gov't"
+content_type: abstract_only
+full_text_attempted: true
+---
+
+# Clinical features of ATRX or DAXX mutated neuroblastoma.
+**Authors:** Kurihara S, Hiyama E, Onitake Y, Yamaoka E, Hiyama K
+**Journal:** J Pediatr Surg (2014)
+**DOI:** [10.1016/j.jpedsurg.2014.09.029](https://doi.org/10.1016/j.jpedsurg.2014.09.029)
+
+## Content
+
+PURPOSE: Previously, we reported that alternative lengthening of telomere (ALT) may be a biomarker for chemo-sensitivity and late recurrence in neuroblastoma (NBL). In this study, alterations of ATRX or DAXX, which both encode chromatin remodeling proteins in telomeric region, and their relationship to ALT were examined in NBLs.
+
+METHODS: Our previous report on 121 NBLs revealed 11 NBLs with elongated telomeres by ALT. In these NBLs, ATRX or DAXX gene alterations were identified using next-generation sequencing and compared to clinical and other biological factors.
+
+RESULTS: In 11 ALT cases, DAXX mutations were detected in one case, and ATRX alterations were detected in 10 cases. Except for one case, no DAXX or ATRX alterations were detected in 110 tumors with normal or shortened telomeres. MYCN amplification was not detected in ATRX altered tumors. In ALT cases, three infants showed ATRX deletions, and all seven cases detected after 18months of age showed poor prognosis.
+
+CONCLUSIONS: In NBLs, ALT was caused by ATRX or DAXX alterations. ATRX altered cases without MYCN amplification detected at greater than 18months showed poor prognosis, suggesting that ATRX or DAXX alterations are a particular NBL subtype. Since these tumors showed chemo-resistance and late recurrence, complete resection in a surgical approach should be performed to improve patient prognosis.